The new edition of this book retains the conventional approach to the classification of bone tumors, dividing them into the categories of osteoblastic, chondroblastic, fibrous and fibroosseous, vascular and neurogenic, and others of mesenchymal tissue derivation. In general, the discussion of the lesions is similar but not identical to the World Health Organization’s classification of bone tumors (Table 1-1). The past decade has been marked by major advancements in our understanding of the molecular biology of sarcomas, and some of these new developments are of diagnostic as well as of potential therapeutic significance. The identification of recurrent chromosomal translocations in many sarcomas, and their application in the differential diagnosis of these tumors, is changing the paradigm of both pathologic and clinical practice. It is surprising and at the same time insightful that such clonal chromosomal translocations and their respective hybrid genes have been identified in several bone and soft tissue lesions that were traditionally considered to be reactive in nature. Dramatic advancement in our understanding of the biology of skeletal-forming cell lineages such as osteoblastic, chondroblastic, and osteoclastic has further expanded the armamentarium of genes and their encoded proteins that may be useful as potential biomarkers in the differential diagnosis of bone tumors. As a consequence, many tumors of uncertain histogenesis have undergone reassessment due to findings from these techniques while the well-defined pathologic entities are undergoing molecular sub-classifications. Ewing’s sarcoma and the family of small round cell malignancies represent a paradigm for the changing practice in skeletal pathology, in which the established diagnostic algorithm based on clinical, radiologic, and microscopic correlations is now coupled with new molecular approaches to delineate this still mysterious group of tumors. TABLE 1-1 WHO Classification of Tumors of Bone* Introduction of newer techniques of immunohistochemistry, molecular pathology, and cytogenetics has not changed the fact that histologic and cytologic characteristics are the basis for classifying bone tumors. Although radiologic features can provide valuable clues about predisposing conditions and mineralization or growth patterns, ultimately bone tumors are microscopically categorized on the basis of cell type and matrix production. The histogenesis of the tumor usually can be deduced from the cell morphology and whether collagen, osteoid, or cartilage matrix production can be identified. The need, originally stressed by Jaffe,1 to regard bone tumors as clinicopathologic entities whose behavior and biologic potential are affected by other clinical factors such as patient age, location in a particular bone or part of a bone, multicentricity, and association with other (underlying) conditions, is reaffirmed. The familiar diagnostic triangle recommended by Jaffe—the surgeon, radiologist, and pathologist sharing their points of view on a bone lesion to arrive at a rational diagnosis—is still valid. This approach, which avoids overemphasis on one aspect of a tumor’s presentation (often leading to disparate opinions), remains as a standard of practice in skeletal pathology. However, the advent of molecular diagnostic techniques has expanded this diagram into a diagnostic quadrangle, as shown in Figure 1-1. The approach of the so-called diagnostic quadrangle postulates a stepwise, analytic approach in which four distinctive data sets—clinical, radiographic, microscopic, and molecular—are considered to establish the diagnosis. Although an intuitive approach based on fragmentary data can occasionally be very impressive when used to arrive at a diagnosis, a stepwise, analytic approach is more likely to lead to consistency and accuracy. For that specific reason, we attempt to describe individual neoplastic lesions of bone with an approach that includes clinicoradiographic, pathologic, and molecular correlations. The description of most lesions is separated into paragraphs including epidemiologic, radiographic, gross, and microscopic data, and pertinent information on any special techniques required for identification is also provided. The frequency distributions in skeletal areas represent approximate compilations based on findings from several major published series. Published data from the Mayo Clinic, Memorial Sloan-Kettering Cancer Center, and The University of Texas M.D. Anderson Cancer Center have been included in the analysis. In addition, national epidemiologic data are provided for the most common malignant bone tumors and are based on the most recent analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. The description of most lesions is accompanied by a graphic presentation of the peak age incidence and their typical sites of skeletal involvement. This should help readers recognize the most typical clinicoradiographic patterns of most bone tumors and tumorlike lesions. The system of graphic depiction of skeletal distribution patterns originally designed by the Mayo Clinic Group is used with some modifications in this book. The intention is to provide a balanced view of current pathogenetic and diagnostic concepts on bone tumors and tumorlike lesions. In reference to several bone lesions the author’s concepts, which may differ from those of others, are presented. In such instances, the controversies are discussed in some detail. Personal opinions in the form of recommendations on the basis of experience as to how to address a particular diagnostic problem are expressed in interspersed paragraphs entitled “Personal Comments.” Discussion of the morphology of the skeletal system is restricted to some basic elements important to the pathologist and helpful in the understanding of basic gross, radiographic, and microscopic features of bone tumors and related conditions described in this text. For more comprehensive descriptions of the structure of the skeletal system, readers should refer to any of the major textbooks and monographs strictly dedicated to this subject. Bone and cartilage represent highly specialized tissues that perform several functions: mechanical, protective, and metabolic. Mechanically, they provide for the integrity of overall body structure and body movements. The protective function of bone is demonstrated by the encasement of several vital organs (lungs, heart, and central nervous system) and of bone marrow, which is the source of blood cells. Metabolically, bone represents a reservoir for several ions, predominantly calcium and phosphorus. Living bone is a highly labile, dynamic tissue that is able to respond to a number of metabolic, physical, and endocrine stimuli. At the same time, its relative simplicity in terms of structural elements allows bone to restore itself to its normal function and architecture after injury. Major topographic regions of the skeleton frequently used in the description of bone tumors are shown in Figure 1-2. The skeleton forming the central axis (skull, vertebral column, and sacrum) is referred to as the axial skeleton.The bones of the extremities (including the scapula and pelvis) are collectively called the appendicular skeleton. The term acral skeleton designates the bones of the hands and feet. In the axial skeleton lesions involving craniofacial bones form a distinct group separate from those of the vertebral column and sacrum. Similarly, in the discussion of neoplastic lesions arising in the scapula and pelvis, these sites are grouped with other bones of the trunk. On the basis of their gross appearance, bones are divided into two main groups: flat and tubular bones. In general, the bones of the trunk and craniofacial region, such as the skull, scapula, clavicle, pelvis, and sternum, are classified as flat. The bones of the extremities and the ribs are tubular. The tubular bones are further subdivided into the long bones (e.g., femur, tibia, humerus) and the short bones (e.g., phalanges, metatarsals, metacarpals) (Figs. 1-3 and 1-4). The carpal and tarsal bones, as well as the patella, are designated as epiphysioid bones, which are analogous to the epiphyses of long bones with regard to development and tumor predilection. The tubular bones have several regions or zones: 2. Metaphysis: The region adjacent to the growth plate opposite the epiphysis 3. Diaphysis or shaft: The region between metaphyses 4. Physis: The region of bone corresponding to the growth plate. Knowledge of these terms and their definitions is very useful because many tumors have a predilection for particular regions of bone (Figs. 1-5 and 1-6). Bone, cartilage, and fibrous connective tissue differ in their visible appearance and mechanical properties because of the various compositions of their matrices.2,7,8,13,14,17,22,30,40 Dense fibrous connective tissue is formed of well-oriented bundles of collagen, and its principal function is to resist tension. Bone and cartilage must also resist compression, torsion, and bending forces. Each bone has a peripheral compact layer known as the cortex (Fig. 1-7). The interior of bone has a network of trabeculae called the cancellous (spongy) or trabecular bone (see Fig. 1-7). The space inside the bone delineated by the cortex is referred to as the medullary cavity. The intertrabecular spaces of the medullary cavity consist of adipose tissue, fibrovascular structures, and hematopoietic tissue. The trabecular bone with its high surface/volume ratio is susceptible to rapid turnover, and hence most sensitively reflects alterations in mineral homeostasis.3,4,16,18 The trabecular bone contributes to skeletal stability by distributing compressive loads across a joint. On the other hand, the diaphyseal cortex resists bending and tension forces. Based on the overall organization of type I collagen fibers bone is categorized into woven and lamellar types.34,43,45 In woven bone, the collagen fibers are haphazardly organized and form an irregular framework. In contrast, in lamellar bone the collagen fibrillary network has an orderly parallel organization. In general, woven bone is produced during rapid bone growth or repair, such as a fracture callus. It represents an immature form of bone in which osteoid is rapidly deposited and is gradually remodeled into a mature lamellar form. The mature lamellar bone, within the cortex, is organized into several distinct architectural patterns referred to as circumferential, concentric, and interstitial. The circumferential lamellar bone forms the outer and inner layer of the cortex. The concentric lamellar bone forms the bulk of the so-called haversian or osteon systems within the cortex. It contains the central canal with blood vessels surrounded by a cylindrical concentric lamellae of bone. The osteocytes within such systems are also somewhat concentrically arranged within the lacunae and are connected by dendritic processes extending outside of the main osteocytes’ bodies via the system of canaliculi that forms an interconnecting mesh within the mineralized matrix. Volkmann’s canals course through the cortex at more perpendicular angles with respect to the haversian systems and contain the connective tissue and feeding vessels that eventually branch into the vasculature of the haversian canals. The microarchitecture of the mineralized deposit and fibrular network is still poorly understood. The recently developed models postulate the tubular nature of basic structural units in which the mineralized plates of hydroxyapatite are connected by helical collagen fibers. (Fig. 1-8) The mineral material provides the structural stiffness of bone but it is the most brittle component that is protected by interfibrillary matrix of protein.19,28,42 The intrafibrillary matrix contains both collagen and non-collagen proteins. The mineralized plates are spatially organized to form fibrils composed of platelets of minerals and intrafibrillary matrix. Cartilage consists of specialized cells (chondrocytes) and an extracellular matrix composed of fibers embedded in an amorphous, eosinophilic, gel-like matrix.15,20,49 On the basis of the matrix composition, cartilage can be divided into three major subtypes: hyaline, fibrous, and elastic. Hyaline cartilage is present at the ends of ribs and covers the joint surfaces. It also is seen in tracheal rings and the larynx. It is composed of collagen fibers and a dense amorphous eosinophilic substance. Fibrocartilage is present at the insertion of tendons. The unique feature of this type of cartilage is its gradual transition to the dense connective tissue of tendons. Elastic cartilage is present in the external and auditory canal, eustachian tube, external ear, and cuneiform cartilage of the larynx. It is characterized by the presence of a rich network of elastic fibers. Elements of the extracellular matrix of the skeletal system, uniquely suited to perform the mechanical function of the skeleton, consist of several major basic components: collagen, proteoglycans, and minerals.5,7,10,13 Metabolically they represent a major body reservoir of several ions, predominantly calcium and phosphorus. Collagen is the most abundant protein in the body and the major organic component of extracellular matrix in bone. The collagen molecule comprises three chains, each of which contains a repeating tripeptide sequence of glycine-x-y, in which x and y are frequently proline and hydroxyproline. These three chains are individually synthesized on ribosomes and subsequently are assembled into a triple helix. The cross-linking among these molecules is responsible for the formation of the fibrillar matrix. The architecture of collagen fibers reflects the integrity of bone and its level of maturation. In normal adults, virtually all bone collagen is deposited in parallel lamellar bundles as seen by polarizing microscopy, hence the term lamellar bone. When metabolism of the skeleton is accelerated and there is need for rapid formation of matrix collagen, its lamellar architecture is lost and replaced by randomly arranged fibers of varying sizes known as woven bone. Woven bone (fiber bone) is formed at sites of early endochondral and membranous ossifications and in fracture callus, periosteal reactions, endosteal healing processes, and rapidly formed tumor bone. The recognition of woven bone and its distinction from mature lamellar bone are greatly facilitated by the use of polarization microscopy. Proteoglycans are the major noncollagenous organic components of skeletal matrices.7,14,20,31,35 They are present in greatest concentrations in cartilage, resulting in its intense metachromasia. Proteoglycans consist of a core of hyaluronic acid with protein side chains lined by a variety of sulfated glycosaminoglycans. They are mainly assembled and sulfated in the Golgi apparatus after the protein moieties have been synthesized by the ribosomes. In the presence of water, the hydrophilic macromolecule of the protein polysaccharide inflates to form a body with a shape analogous to a test tube brush with the consistency of a stiff gel. The size and consistency of the hydrated molecule are responsible for many of the mechanical and physicochemical properties of cartilage. The bony skeleton is made rigid by the addition of mineral to the deposited extracellular organic matrix.2,8,10,13,31 The inorganic phase of mature bone mineral is a carbonate-containing analog of hydroxyapatite [Ca10 (PO4)6 (OH)2] that forms submicroscopic irregular crystals. The precise mechanism of mineral deposition in the skeleton is not clear, but there is evidence that the organic components of bone play a role in the process. On its initial appearance in the skeleton, calcium phosphate exists in a relatively poorly crystallized form. In lamellar bone, it is deposited at the interface of osteoid and mineralized tissue. The lamellar maturation of bone is associated with conversion of the mineralized deposits into a hydroxyapatite with a more distinct crystalline pattern. The cells of the skeleton system include osteoblasts, osteocytes, osteoclasts, chondroblasts, and chondrocytes (Fig. 1-9). Osteoblasts are specialized cells that synthesize the bone matrix.6,25,41,44 They are cuboidal or columnar and are invariably found lining osteoid seams. They most likely arise from precursor cells present in the peritrabecular marrow. Osteoblasts have a prominent Golgi apparatus and are rich in rough endoplasmic reticulum, resulting in prominent basophilia. These features reflect their active participation in mineralization and in the process of organic matrix production. Osteoblasts contain large amounts of alkaline phosphatase. When engaged in the synthesis of lamellar bone, osteoblasts are polarized in relationship to the underlying osteoid seam. In woven bone, this orderly anatomic arrangement of osteoblasts is absent. Although there is no question that osteoblasts as just described actively synthesize bone, most bone surfaces are covered by flat, fusiform cells, variously called inactive osteoblasts or bone-lining cells. These cells are capable of skeletal synthesis at a slower rate than activated cuboidal or columnar osteoblasts. They also may act as a barrier that separates the bone fluid compartment both anatomically and functionally from the general extracellular fluid. Osteocytes represent specialized cells that have been incorporated into the bone matrix. They are involved in the maintenance and turnover of bone at a slow rate (i.e., slower than activated osteoblasts).9,24,27,29 They are the most numerous of bone cells and, with their cytoplasmic processes, which extend through canaliculi, constitute the major portion of the bone cell syncytium. Young osteocytes often resemble osteoblasts ultrastructurally. They are capable of perilacunar matrix synthesis and mineralization, which result in progressive diminution of lacunar size. Osteocytes that are older and hence deeper in the matrix may assume osteoclastic features and resorb bone. Osteoclasts are large, multinucleated cells that are responsible for the resorption of bone and calcified cartilage.11,12,26,32,33,36,44 An abundance of enzymes that play a role in bone lytic activities, including acid phosphatase and various proteolytic enzymes such as collagenases, is present in these cells. Osteoclasts are derived from the monocyte macrophage precursors and share some of their antigenic features. Osteoclasts have a convoluted cell membrane, or “ruffled border,” that is juxtaposed to the bone surface. The formation of the ruffled border and its adherence to the bone surface are stimulated by parathormone and inhibited by calcitonin. In addition, the activity of osteoclasts is mediated by several ubiquitous cytokines. Chondroblasts represent immature cells of cartilage and are precursors of chondrocytes.15,20,25 They are typically not seen in the adult normal skeleton. During fetal development, areas of cartilaginous differentiation occur within mesenchymal tissue. The earliest forms of chondroblastic differentiation are difficult to recognize microscopically because they do not differ significantly from fetal myxoid mesenchymal tissue. However, they are at least weakly positive for S-100 protein, an immunohistochemical hallmark of cartilaginous differentiation that is expressed on all cells of cartilage lineage. Young cartilage cells are relatively small compared with chondrocytes. They may have a flattened or irregular contour, and the surface may show multiple projections or filopodia. The nucleus usually contains a prominent nucleolus, and it may show a prominent paranuclear Golgi zone. A pericellular lacuna is usually absent or indistinct, and the amount of intercellular matrix is less abundant than that associated with chondrocytes. In general, immature cartilage is highly cellular. The morphology of immature cartilage cells is best studied in lesions that recapitulate embryonal stages of cartilaginous differentiation, such as chondromyxoid fibroma, chondroblastoma, clear cell chondrosarcoma, and myxoid chondrosarcoma. A prototype chondroblast is a cell typically seen in a benign cartilage tumor designated as chondroblastoma. It has a dense eosinophilic cytoplasm with an oval nucleus that has a prominent longitudinal groove, often seen under light microscopic examination. Chondrocytes represent mature cartilage cells that are derived from mesenchymal precursor cells.15,20,46 They are located in lacunae surrounded by the cartilaginous matrix. Chondrocytes tend to be clustered in small, loose groups that are isogenous or monoclonal because they represent progeny of a single chondrocyte. In the epiphyseal plates of long bones, the cartilage cells are arranged in long columns. During the skeletal growth phase, cartilage cells in the epiphyseal plates undergo transient proliferative activity followed by deposition of a cartilaginous matrix and programmed cell death (apoptosis). Proliferation of cartilage cells followed by apoptosis is the most important mechanism governing skeletal growth. Mature chondrocytes have small, dense nuclei. Open nuclear chromatin with small nucleoli is present in proliferating cartilage cells. The ultrastructure of chondrocytes is characterized by numerous branched cytoplasmic processes, a well-developed endoplasmic reticulum, and a Golgi center. Fetal bone formation and postnatal growth occur in one of two ways. In intramembranous ossification, clusters of fetal mesenchymal cells differentiate directly into osteoblasts. In enchondral bone formation, a predeposited cartilaginous matrix (cartilage model) serves as a scaffold for the deposition of osteoid (Fig. 1-10). In the developing epiphyseal centers, this cartilage model undergoes focal calcification, followed by vascular invasion and the appearance of bone-synthesizing osteoblasts.21,23,38,39 Thus the cartilaginous matrix is replaced by bone, except at the growth plate and articular surfaces.37–39 At the mesenchymal-vascular junction of the epiphyseal growth plate and metaphyseal bone, invasion of continuously growing cartilage is followed by osteoblastic differentiation and deposition of osteoid. The devitalized, calcified cartilage serves as a scaffolding for the deposition of bone matrix and is resorbed by osteoblasts at the same rate at which the growth plate is internally expanded. Consequently, long bone growth occurs while the thickness of the epiphyseal plate remains constant. The cessation of interstitial expansion of the epiphyseal plate results in its gradual obliteration and the termination of growth. Cartilage serves as the mediator of long bone growth because it is capable of interstitial matrix deposition and surface apposition. Intramembranous bone formation first appears as many separate centers of ossification that enlarge and fuse to form a single plate (Fig. 1-11). Membranous bones are directly formed from the mesenchymal tissue without a preexisting cartilage model. Growth in the diameter of a bone continues principally by the deposition of osteoid on the outer convex surface of the shaft through membranous ossification in the cambium layer of the periosteum. Tubulation and remodeling are achieved by osteoclastic activity resorption on the inner concave surface.
General Considerations
Introduction
Tumor
Code
Chondrogenic Tumors
Benign
Osteochondroma
9210/0
Chondroma
9220/0
Enchondroma
9220/0
Periosteal chondroma
9221/0
Osteochondromyxoma
9211/0
Subungual exostosis
9213/0
Bizarre parosteal osteochondromatous proliferation
9212/0
Synovial chondromatosis
9220/0
Intermediate (locally aggressive)
Chondromyxoid fibroma
9241/0
Atypical cartilaginous tumor
Chondrosarcoma grade 1
9222/1
Intermediate (rarely metastasizing)
Chondroblastoma
9230/1
Malignant
Chondrosarcoma
Chondrosarcoma grade 2, grade 3
9220/3
Dedifferentiated chondrosarcoma
9243/3
Mesenchymal chondrosarcoma
9240/3
Clear cell chondrosarcoma
9242/3
Osteogenic Tumors
Benign
Osteoma
9180/0
Osteoid osteoma
9191/0
Intermediate (locally aggressive)
Osteoblastoma
9200/0
Malignant
Low-grade central osteosarcoma
9187/3
Conventional osteosarcoma
9180/3
Chondroblastic osteosarcoma
9181/3
Fibroblastic osteosarcoma
9182/3
Osteoblastic osteosarcoma
9180/3
Telangiectatic osteosarcoma
9183/3
Small cell osteosarcoma
9185/3
Secondary osteosarcoma
9184/3
Parosteal osteosarcoma
9192/3
Periosteal osteosarcoma
9193/3
High-grade surface osteosarcoma
9194/3
Myogenic Tumors
Benign
Leiomyoma of bone
8890/3
Malignant
Leiomyosarcoma of bone
8890/3
Lipogenic Tumors
Benign
Lipoma of bone
8850/0
Malignant
Liposarcoma of bone
8850/3
Tumors of Undefined Neoplastic Nature
Benign
Simple bone cyst
8818/0
Fibrous dysplasia
Osteofibrous dysplasia
Chondromesenchymal hamartoma
Rosai-Dorfman disease
Fibrogenic Tumors
Intermediate (locally aggressive)
Desmoplastic fibroma of bone
8823/1
Malignant
Fibrosarcoma of bone
8810/3
Fibrohistiocytic Tumors
Benign
Benign fibrous histiocytoma/non-ossifying fibroma
8830/0
Hematopoietic Neoplasms
Malignant
Plasma cell myeloma
9732/3
Solitary plasmacytoma of bone
9731/3
Primary non-Hodgkin lymphoma of bone
9591/3
Osteoclastic Giant Cell Rich Tumors
Benign
Giant cell lesion of the small bones
Intermediate (locally aggressive, rarely metastasizing)
Giant cell tumor of bone
9250/1
Malignant
Malignant giant cell tumor of bone
9250/3
Notochordal Tumors
Benign
Benign notochordal tumor
9370/0
Malignant
Chordoma
9370/3
Vascular Tumors
Benign
Hemangioma
9120/0
Intermediate (locally aggressive, rarely metastasizing)
Epithelioid hemangioma
9125/0
Malignant
Epithelioid hemangioendothelioma
9133/3
Angiosarcoma
9120/3
Intermediate (locally aggressive)
Aneurysmal bone cyst
9260/0
Langerhans cell histiocytosis
Monostotic
9752/1
Polystotic
9753/1
Erdheim-Chester disease
9750/1
Miscellaneous Tumors
Ewing’s sarcoma
9364/3
Adamantinoma
9261/3
Undifferentiated high-grade pleomorphic sarcoma of bone
8830/3
Morphology of Normal Bone
Topographic Features
Bone
Cartilage
Extracellular Matrix
Collagen
Proteoglycans
Bone Mineral
Cells
Osteoblasts
Osteocytes
Osteoclasts
Chondroblasts
Chondrocytes
Development of Bone
General Considerations
Chapter 1
FIGURE 1-3 Development of bone. Development of primary ossification center in a long bone (tibia). Cartilaginous epiphyses at both ends are remnants of cartilage model. Center has been replaced by developing diaphysis with zones of enchondral ossification at both ends. At this stage primary spongiosa with active enchondral ossification occupies most of the bone length within the metaphyseal portions while the developing shaft is a relatively minor component of the length. Secondary ossification centers will develop in cartilage masses at bone ends, and continued ossification will lead to formation of growth plates (physis) (see Fig. 1-5).
